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IBI Test 4 > B3.059 Cell Signaling in the Immune System > Flashcards

B3.059 Cell Signaling in the Immune System Flashcards

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1
Q

what are the 3 steps in signal transduction

A
  1. signal perception upon ligand binding
  2. intracellular signal transduction
  3. cellular response
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2
Q

common themes in signal transduction

A

conformational change of proteins
post-translational modification of proteins
protein movement within a cell (translocation)
protein-protein interactions
second messengers
altered gene transcription
pathway downregulation

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3
Q

3 major classes of kinases

A

receptor tyrosine kinases
non-receptor tyrosine kinases (JAK)
MAPK

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4
Q

what is the primary function of kinases/phosphatases

A

molecular switches for turning cells on and off again

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5
Q

how does phosphorylation occur

A

each phosphate group carries 2 negative charges

major conformational change in the protein by attracting a cluster of positively charged amino acid side chains

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6
Q

what is the affect of the conformational change induced by phosphorylation

A
  1. affects the binding of ligands elsewhere on the protein surface, changing the proteins activity
  2. attached phosphate group can form part of a structure that the binding sites of other proteins recognize (SH2, SH3)
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7
Q

what receptor exhibits kinase activity

A

growth factor receptors

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8
Q

what receptors are associated (non covalently) with kinases

A

associated all the time
-cytokine receptors
associate with receptor after ligand binding
-antigen receptors (BCR, TCR)

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9
Q

how do receptors with intrinsic or associated kinase domains work

A

ligand binding dimerizes the receptor, activating the kinases which phosphorylate each other
activated kinases phosphorylate downstream substrates

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10
Q

discuss the physical structure of JAKs

A

Janus Kinase
-has 2 near identical phosphate transferring domains, one w kinase activity and one that negatively regulates the kinase activity
proline rich region of membrane proximal receptor (Box 1/ box 2 domain)

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11
Q

what are the JAKs

A

JAK1-4, TYK2

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12
Q

what are STATs

A

signal transducers and activators of transcription

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13
Q

classify STATs

A

7 members in mammals

STAT 1-4, 5a and b, 6

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14
Q

discuss the binding properties of STATs

A 
phosphorylated by JAK, RTK, c-src
bind GAS (gamma activated sites) or ISREs
homo/heterodimerize via SH2 domains post phosphorylation
coiled-coil domain = nuclear localization signal
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15
Q

which cytokines utilize JAK1 and JAK3

A

IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, IL-21R

have shared gamma subunit

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16
Q

cytokines that activate STAT1

A

type 1 IFNs and IFN-y

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17
Q

cytokines that activate STAT2

A

type 1 IFNs

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18
Q

cytokines that activate STAT3

A

may

esp gp130 cytokines

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19
Q

cytokines that activate STAT4

A

IL-12

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20
Q

cytokines that activate STAT5a and b

A

IL-2

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21
Q

cytokines that activate STAT6

A

IL-4

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22
Q

depict the general model of signal transduction mediated by most class 1 and 2 cytokine receptors

A
  1. binding of cytokine causes dimerization of receptors and activation of JAK kinases
  2. activated JAK kinases phosphorylate receptor sites and create docking sites for STAT molecules
  3. phosphorylation of STAT by JAK kinase
  4. the phosphorylated STATs dimerize and translocate to the nucleus where they activate transcription of specific genes
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23
Q

proteins involved in type 1 interferon signaling

A

IFNa, B
JAK1, TYK2
STAT1-STAT2
antiviral response

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24
Q

proteins involved in type 2 interferon signaling

A

IFNy
JAK1, JAK2
STAT1- STAT1

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25
what are the components of the IL2 high affinity receptor
IL2Ra, IL2RB | gamma common chain (CD132)
26
proteins involved in IL2 signaling
JAK1, JAK3 ( JAK3 always bound to gamma c chain) STAT5a and b Ras PIP2/IP3/DAG
27
describe JAK3 X-linked SCID
JAK3 is essential for cytokine signaling mediated by gamma c cytokines mutations lead to inactivation of signaling pathways no T or NK cells, but normal B cell numbers cytokines are required for development of T and NK cell types
28
what does kinase driven phosphorylation provide
docking sites for SH2 domain-containing receptors and platforms on which signaling cascades are established
29
how is the JAK/STAT pathway negatively regulated?
phosphatases/molecules which prevent phosphorylation
30
what are the primary classes of phosphatases/molecules which prevent phosphorylation
``` SHP1, SHP2 (SH2 domain) SHIP (SH2 domain) CD45 SOCS PIAS ```
31
non receptor protein tyrosine phosphatases
SHP1, SHP2
32
inositol phosphatase
SHIP
33
receptor tyrosine phosphatase
CD45
34
prevent further phosphorylation
SOCS | PIAS
35
remove phosphates directly
SHP1, SHP2 SHIP CD45
36
how does PIAS work
protein inhibitors of activated STAT inhibit STAT1 and STAT3 binding and blocking access to GAS
37
what is a SOCS
suppressors of cytokine signaling
38
what are the 3 primary domain structures of SOCS1 and SOCS3
KIR classical SH2 SOCS box
39
what does the KIR do
inhibit JAK kinase activity directly binds activation loop of JAK catalytic domain functions as a psuedosubstrate
40
what does the SH2 domain do
for binding to phosphorylated receptor and/or phosphorylated JAKs (docking)
41
what does the SOCS box do
target entire cytokine receptor complex, including JAKS and SOCS themselves for ubiquitin mediated proteasomal degradation
42
how can the SOCS family shape macrophage polarity
high SOCS1 to SOCS3 ratio associated with M2 macrophage polarization high SOCS3 associate with M1 macrophage polarization based on selective inhibition of signaling pathways
43
Ruxolitinib
inhibits JAK1, JAK2 reduces spleen size (site of extramedullary hematopoiesis) treats myelofibrosis
44
Tofacitinib
inhibits JAK3 interferes with IL2 and IL4 signaling approved for treatment of rheumatoid arthritis
45
what are the innate immune sensors
TLRs, RIGI like receptors, NOD like receptors
46
what are the most important innate immune sensors
TLRs | on macrophages, dendritic cells, and others
47
what do TLRs detect
``` wide range of ligands bacterial, viral, fungal ECM fragments nucleic acids intracellular proteins ```
48
what 2 intracellular signaling pathways does TLR4 utilize
Myd88-dependent (fast, 2-5 min) Myd88-independent (TRIF-dependent) (slow, hour) both activate NF-kB
49
what is required for NF-kB mediated gene transcription
phosphorylation of IkB by IKK complex to liberate NFkB | only then can NFkB translocate to the nucleus to regulate gene transcription
50
what does TLR4 recognize
LPS
51
CD4+ T cell effector functions
1. CD4+ binds MHC class 2 2. both CD4+ cell and APC release cytokines 3. cytokines cause T cell to cone itself 4. clonal T cells produce different cytokines to activate B cells and CD8+ T cells
52
CD8+ T cell effector functions
1. CD8+ cell binds MHC class 1 and produces granzymes and perforins 2. perforins form pores in plasma membrane, granzymes enter the cell and break down proteins, lysing the cell
53
describe the process of proximal T cell signaling
1. TCR sees Ag in the context of MHC 2. CD4/CD8 is associated with Lck 3. binding causes dissociation of CD45 p-tase 4. Lck activated and phosphorylates 10 ITAMs in CD3 chains 5. Zap70 docks to phosphorylated CD3 zeta chain 6. Lck phosphorylates Zap70 (active) 7. Zap70 autophosphorylates 8. Zap70 phosphorylates many linker/adaptor proteins of the distal T cell activation pathway
54
what are the 2 primary proteins involved in distal T cell signaling
LAT and SLP-76 phosphorylated by zap70 initiate 4 downstream pathways
55
what are the 4 downstream signaling modules of distal T cell signaling
1. Akt-mediated increase in metabolic activity 2. PLCy-mediated increases in calcium and IL2 production 3. Vav activation and cytoskeletal reorganization 4. ADAP recruitment integrin activation/clustering to improve adhesion
56
why is IL2 so important for T cells
promotes cell growth promotes cell survival promotes differentiation into effector cells promotes differentiation into memory cells required for T reg development
57
2 important signaling molecules generated by PLC-y
PIP3 | DAG
58
what does PIP3 do
opens calcium channels to allow Ca2+ release from the ER into cytosol leads to STIM1 aggregation STIM1 aggregation opens a channel allowing entry of extracellular calcium
59
what does DAG do
activates PCK which is required for NFkB activation
60
what is NF-AT
transcription factor regulated by calcium signaling
61
discuss the regulation of NF-AT
1. phosphorylation on serine and threonine residues keeps NFAT in the cytoplasm of unstimulated cells 2. calcium entry activates the serine/threonine phosphatase calcineurin which dephosphorylates NFAT 3. dephosphorylated NFAT enters the nucleus and activates gene transcription (IL2)
62
calcineurin inhibitors
cyclosporine, tacrolimus promote graft survival after liver transplant prevents dephosphorylation of NFAT suppress IL2 transcription
63
mechanism of cyclosporine (CsA)
1. CsA binds cyclophilin (CpN) 2. complex bind and blocks function of calcineurin 3. downstream signaling cannot produce IL2 full T cell activation prevented
64
mechanism of tacrolimus (FK506)
1. FK506 binds FK506-binding protein (FKBP) 2. binds and blocks CaN 3. downstream signaling cannot produce IL2 full T cell activation prevented
65
what co stimulatory molecules provide signals for T cell activation
CD28: B7-1/2 CD40: CD40L ICOS:ICOSL
66
what co stimulatory molecules provide signals for T cell down regulation
CTLA4: B7-1/2 PD-1:PD-L1/2 BTLA:HVEM
67
how does CTLA4 work
outcompetes CD28 for binding
68
ipilimumab
``` targets CTLA4 (cytotoxic T lymphocyte associated protein 4) melanoma NSCLC, SCLC, bladder cancer metastatic, hormone refractory prostate cancer ```
69
pembrolizumab
targets PD-1 (programmed cell death) any unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsattelite instability high state
70
suppressing the immune system with Treg cells
maintain self tolerance suppressing self reactive lymphocytes that recognize Ag different from those recognized by the conventional T cells intermediate affinity for self MHC: peptide complexes
71
proteins expressed by Treg cells
CD4+, Foxp3+, CTLA4 high, TGFB, IL10, IL35
72
why do Treg cells require IL2
development and for suppressive activity
73
mutations in Treg cells can cause what
IPEX (immune dysregulation, polyimmune endocrinpathy, enteropathy, X-linked)
74
describe T cell anergy
signal 1 without signal 2 an inactive state mechanism of immunological tolerance cancers often downregulate molecules that provide signal 2
75
what is the outcome of B cell activation
``` Ig class switching terminal differentiation into Ab-secreting plasma cells production of memory B cells with or without T cell help as defined in the next slides ```
76
describe T cell independent B cell activation
TLR/PAMP/DAMP interaction | activation of B cell and secretion of pentameric IgM
77
describe T cell dependent B cell activation
cytokines produces by CD4+ T cells stimulate clonal expansion and production of memory B and plasma cells
78
describe the overarching steps in B cell signaling via the BCR
1. cross linking of membrane Ig by antigen 2. tyrosine phosphorylation events 3. biochemical intermediates 4. active enzymes 5. transcription factors (NFAT, NF-kB, AP-1)

IBI Test 4 (21 decks)

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